scholarly journals Therapeutic Strategies to Target Calcium Dysregulation in Alzheimer’s Disease

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2513
Author(s):  
Maria Calvo-Rodriguez ◽  
Elizabeth K. Kharitonova ◽  
Brian J. Bacskai
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Types ◽  
Therapeutic Strategies ◽  
Neuronal Function ◽  
Calcium Dysregulation ◽  
Disease Mechanisms ◽  
Chemical Agents ◽  
The Brain ◽  
Ca2 Channels

Alzheimer’s disease (AD) is the most common form of dementia, affecting millions of people worldwide. Unfortunately, none of the current treatments are effective at improving cognitive function in AD patients and, therefore, there is an urgent need for the development of new therapies that target the early cause(s) of AD. Intracellular calcium (Ca2+) regulation is critical for proper cellular and neuronal function. It has been suggested that Ca2+ dyshomeostasis is an upstream factor of many neurodegenerative diseases, including AD. For this reason, chemical agents or small molecules aimed at targeting or correcting this Ca2+ dysregulation might serve as therapeutic strategies to prevent the development of AD. Moreover, neurons are not alone in exhibiting Ca2+ dyshomeostasis, since Ca2+ disruption is observed in other cell types in the brain in AD. In this review, we examine the distinct Ca2+ channels and compartments involved in the disease mechanisms that could be potential targets in AD.

scholarly journals Peptides Derived from Growth Factors to Treat Alzheimer’s Disease

2021 ◽  
Vol 22 (11) ◽  
pp. 6071
Author(s):  
Suzanne Gascon ◽  
Jessica Jann ◽  
Chloé Langlois-Blais ◽  
Mélanie Plourde ◽  
Christine Lavoie ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Growth Factors ◽  
Signaling Pathways ◽  
Brain Structures ◽  
Therapeutic Strategies ◽  
Native Proteins ◽  
Receptor Sites ◽  
The Brain

Alzheimer’s disease (AD) is a devastating neurodegenerative disease characterized by progressive neuron losses in memory-related brain structures. The classical features of AD are a dysregulation of the cholinergic system, the accumulation of amyloid plaques, and neurofibrillary tangles. Unfortunately, current treatments are unable to cure or even delay the progression of the disease. Therefore, new therapeutic strategies have emerged, such as the exogenous administration of neurotrophic factors (e.g., NGF and BDNF) that are deficient or dysregulated in AD. However, their low capacity to cross the blood–brain barrier and their exorbitant cost currently limit their use. To overcome these limitations, short peptides mimicking the binding receptor sites of these growth factors have been developed. Such peptides can target selective signaling pathways involved in neuron survival, differentiation, and/or maintenance. This review focuses on growth factors and their derived peptides as potential treatment for AD. It describes (1) the physiological functions of growth factors in the brain, their neuronal signaling pathways, and alteration in AD; (2) the strategies to develop peptides derived from growth factor and their capacity to mimic the role of native proteins; and (3) new advancements and potential in using these molecules as therapeutic treatments for AD, as well as their limitations.

scholarly journals Alzheimer's disease-associated TM2D genes regulate Notch signaling and neuronal function in Drosophila

2021 ◽  
Author(s):  
Jose L Salazar ◽  
Sheng-An Yang ◽  
Yong Qi Lin ◽  
David Li-Kroeger ◽  
Paul C Marcogliese ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gene Family ◽  
Notch Signaling ◽  
Rare Variants ◽  
Neuronal Function ◽  
Evolutionarily Conserved ◽  
Cleavage Step ◽  
The Brain ◽  
Entire Gene

TM2 domain containing (TM2D) proteins are conserved in metazoans and encoded by three separate genes in each species. Rare variants in TM2D3 are associated with Alzheimer's disease (AD) and its fly ortholog almondex is required for embryonic Notch signaling. However, the functions of this gene family remain elusive. We knocked-out all three TM2D genes (almondex, CG11103/amaretto, CG10795/biscotti) in Drosophila and found that they share the same maternal-effect neurogenic defect. Triple null animals are not phenotypically worse than single nulls, suggesting these genes function together. Overexpression of the most conserved region of the TM2D proteins acts as a potent inhibitor of Notch signaling at the γ-secretase cleavage step. Lastly, Almondex is detected in the brain and its loss causes shortened lifespan accompanied by progressive electrophysiological defects. The functional links between all three TM2D genes are likely to be evolutionarily conserved, suggesting that this entire gene family may be involved in AD.

scholarly journals Neuronal expression of STM2 mRNA in human brain is reduced in Alzheimer's disease.

1996 ◽  
Vol 44 (11) ◽  
pp. 1215-1222 ◽  
Author(s):  
P J McMillan ◽  
J B Leverenz ◽  
P Poorkaj ◽  
G D Schellenberg ◽  
D M Dorsa
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Brain ◽  
Basal Forebrain ◽  
Cell Types ◽  
Hybridization Histochemistry ◽  
In Situ Hybridization Histochemistry ◽  
A Cell ◽  
The Brain

Mutations in the STM2 gene cause familial Alzheimer's disease (AD) in Volga Germans. To understand the function of this protein and how mutations lead to AD, it is important to determine which cell types in the brain express this gene. In situ hybridization histochemistry indicates that STM2 expression in the human brain is widespread and is primarily neuronal. In addition, STM2 mRNA is expressed in a cell line with neuronal origins. Quantification of the level of expression of the STM2 message in the basal forebrain, frontal cortex, and hippocampus reveals a significant decrease in AD-affected subjects compared to normal age-matched controls. These data suggest that downregulation of neuronal STM2 gene expression may be involved in the progression of AD.

Are Biomarkers Valid as Surrogates for Treatment Effects in Alzheimer’s Disease?

2009 ◽  
Vol 4 (1) ◽  
pp. 13
Author(s):  
Philip Scheltens ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Treatment Efficacy ◽  
Laboratory Tests ◽  
Neuropsychological Testing ◽  
Neuronal Loss ◽  
Therapeutic Strategies ◽  
Disease Course ◽  
Amyloid Beta Protein ◽  
The Brain

Diagnosis of Alzheimer’s disease (AD), the most common form of dementia, involves neuropsychological testing, limited laboratory tests and brain imaging. Current therapeutic options for AD are symptomatic treatments that target dysfunctional neurotransmitters associated with the disorder. Recent research has focused on therapeutic strategies that inhibit the production and aggregation of amyloid beta protein (Aβ) in plaques and increase its clearance from the brain. Such strategies are likely to be most effective at pre-clinical stages of the disease, before widespread synaptic and neuronal loss occurs. Thus, there is a need for biomarkers that predict disease course and outcome and monitor disease progression and treatment efficacy. The development of such biomarkers for AD is critical to translating the efficacy of new therapies.

scholarly journals The potential role for sphingolipids in neuropathogenesis of Alzheimer’s disease

2013 ◽  
Vol 59 (1) ◽  
pp. 25-50 ◽  
Author(s):  
A.V. Alessenko
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Functional Role ◽  
Potential Role ◽  
Early Stage ◽  
New Drugs ◽  
Neuronal Function ◽  
Sphingosine 1 Phosphate ◽  
The Brain

The review discusses the functional role of sphingolipids in the pathogenesis of Alzheimer's disease. Certain evidence exist that the imbalance of sphingolipids such as sphingomyelin, ceramide, sphingosine, sphingosine-1-phosphate and galactosylceramide in the brain of animals and humans, in the cerebrospinal fluid and blood plasma of patients with Alzheimer's disease play a crucial role in neuronal function by regulating growth, differentiation and cell death in CNS. Activation of sphingomyelinase, which leads to the accumulation of the proapoptotic agent, ceramide, can be considered as a new mechanism for AD and may be a prerequisite for the treatment of this disease by using drugs that inhibit sphingomyelinase activity. The role of sphingolipids as biomarkers for the diagnosis of the early stage of Alzheimer's disease and monitoring the effectiveness of treatment with new drugs is discussed.

scholarly journals Soluble forms of tau are toxic in Alzheimer’s disease

2012 ◽  
Vol 3 (3) ◽  
Author(s):  
Katherine Kopeikina ◽  
Bradley Hyman ◽  
Tara Spires-Jones
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurofibrillary Tangles ◽  
Neuronal Death ◽  
Therapeutic Strategies ◽  
The Brain

AbstractAccumulation of neurofibrillary tangles (NFT), intracellular inclusions of fibrillar forms of tau, is a hallmark of Alzheimer’s disease. NFT have been considered causative of neuronal death, however, recent evidence challenges this idea. Other species of tau, such as soluble misfolded, hyperphosphorylated, and mislocalized forms, are now being implicated as toxic. Here we review the data supporting soluble tau as toxic to neurons and synapses in the brain and the implications of these data for development of therapeutic strategies for Alzheimer’s disease and other tauopathies.

scholarly journals Genetic deletion of soluble epoxide hydrolase delays the progression of Alzheimer’s disease

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Hsueh-Te Lee ◽  
Kuan-I Lee ◽  
Chia-Hui Chen ◽  
Tzong-Shyuan Lee
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Translational Regulation ◽  
Epoxide Hydrolase ◽  
Cell Types ◽  
Soluble Epoxide Hydrolase ◽  
Small Gtpase ◽  
Activated T Cells ◽  
Genetic Ablation ◽  
The Brain

Abstract Background Soluble epoxide hydrolase (sEH) is a bifunctional enzyme with COOH-terminal hydrolase and NH2-terminal lipid phosphatase activities. It is expressed in various cell types in the brain and is involved in the pathogenesis of inflammatory and neurodegenerative diseases. Alzheimer’s disease (AD) is a progressive neuroinflammatory and neurodegenerative disease. However, the pathological significance of sEH and underlying molecular mechanism in AD remain unclear. Methods To examine the role of sEH in pathogenesis of AD, we used wild-type (WT) mice, soluble epoxide hydrolase deficient (sEH−/−) and two mouse models of AD, including amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic (APP/PS1 Tg) and APP/PS1 Tg/sEH−/− mice. Western blotting analysis and immunohistochemistry assay were performed to evaluate the protein expression. Locomotion, nesting building ability, Y-maze, and Morris water maze tests were conducted to study mouse behavior. The levels of interleukin (IL)-1β, IL-4, IL-6, and IL-10 and the activities of NF-κB and nuclear factor of activated T cells (NFAT) were measured by commercial assay kits. The quantitative protein level profiling in the brain lysate was analyzed using LC-MS/MS approaches. Results We demonstrated that the level of sEH was increased in the brain and predominantly appeared in hippocampal astrocytes of APP/PS1 Tg mice. Genetic ablation of sEH in APP/PS1 Tg mice delayed the progression of AD as evidenced by the alleviation in behavior outcomes and Aβ plaque deposition. In addition, loss of the function of sEH in APP/PS1 Tg mice increased astrogliosis and the production of astrocyte-derived anti-inflammatory cytokines including IL-1β, IL-4, and IL-10, as well as the activity of NF-kB and NFAT. Moreover, analysis of gene ontology in the AD brain revealed that important signaling pathways and processes related to AD pathogenesis such as translational regulation, oxidative stress, cytoskeleton reorganization, and small GTPase signal transduction were altered in APP/PS1 Tg/sEH−/− mice compared with APP/PS1 Tg mice. Conclusion Our results suggest that sEH is a crucial regulator in the progression of AD and might be a potential therapeutic target for the treatment of AD.

scholarly journals USING NEURAL NETWORK TO UNCOVER CELL TYPES THROUGH SNRNA SEQUENCING

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S834-S834
Author(s):  
Fahad Paryani ◽  
Vilas Menon
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Types ◽  
Learning Approaches ◽  
Post Mortem Brain ◽  
Single Nucleus ◽  
General Classifier ◽  
Classification Tool ◽  
Genetic Signatures ◽  
The Brain

Abstract The advent of single-nucleus RNA-sequencing (snRNAseq) has allowed for the exploration of genetic signatures of the numerous cells in the brain. In particular, snRNAseq data can provide new insights into how many neurodegenerative diseases, such as Alzheimer’s Disease, alter cells in the brain. One major challenge with analyzing snRNAseq data is the lack of a systematic way to classify the various cell types across different datasets. To address this challenge, we developed a general classifier (“DeepSeq”) that uses state-of-the-art deep learning approaches. We trained our model on multiple snRNAseq datasets derived from post-mortem brain tissue in individuals with and without clinical diagnosis of Alzheimer’s Disease from the ROSMAP cohorts. The two snRNAseq datasets contained 70,064 nuclei and 170,275 nuclei. The two studies employed different clustering techniques, and identified 44 and 18 putative cell types. To map these disparate cluster identities across datasets, we extracted the most relevant genes and trained two separate networks, one on each dataset. We then validated each classifier separately on the holdout cells. The resulting classifier accuracy were 87% and 94%. To map clusters across datasets, we then applied each classifier to the other dataset. Both classifiers yielded mappings that reflected the overall biology, correctly categorizing the nuclei into broad and fine cell type classes. Although validation on additional datasets would expand the generality of this approach, our results show that DeepSeq is an easily implementable classification tool that can assign identity to nuclei in new snRNAseq datasets without the need for preprocessing or cross-batch alignment.

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